Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells

Paolo Mellini; Biagina Marrocco; Diana Borovika; Lucia Polletta; Ilaria Carnevale; Serena Saladini; Giulia Stazi; Clemens Zwergel; Peteris Trapencieris; Elisabetta Ferretti; Marco Tafani; Sergio Valente; Antonello Mai

doi:10.1098/rstb.2017.0150

Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells

Paolo Mellini, Biagina Marrocco, Diana Borovika, Lucia Polletta, Ilaria Carnevale, Serena Saladini, Giulia Stazi, Clemens Zwergel, Peteris Trapencieris, Elisabetta Ferretti, Marco Tafani, Sergio Valente, Antonello Mai

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Abstract

Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4,6-dimethyl-2-oxo-1,2-dihy-dropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy.

Original language	English
Article number	20170150
Journal	Philosophical Transactions of the Royal Society B: Biological Sciences
Volume	373
Issue number	1748
DOIs	https://doi.org/10.1098/rstb.2017.0150
State	Published - Jun 5 2018
Externally published	Yes

Keywords

Apoptosis
Autophagy
Enhancer of zeste homologue 2 inhibitors
Epigenetics

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10.1098/rstb.2017.0150

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Mellini, P., Marrocco, B., Borovika, D., Polletta, L., Carnevale, I., Saladini, S., Stazi, G., Zwergel, C., Trapencieris, P., Ferretti, E., Tafani, M., Valente, S., & Mai, A. (2018). Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells. Philosophical Transactions of the Royal Society B: Biological Sciences, 373(1748), Article 20170150. https://doi.org/10.1098/rstb.2017.0150

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title = "Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells",

abstract = "Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4,6-dimethyl-2-oxo-1,2-dihy-dropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy.",

keywords = "Apoptosis, Autophagy, Enhancer of zeste homologue 2 inhibitors, Epigenetics",

author = "Paolo Mellini and Biagina Marrocco and Diana Borovika and Lucia Polletta and Ilaria Carnevale and Serena Saladini and Giulia Stazi and Clemens Zwergel and Peteris Trapencieris and Elisabetta Ferretti and Marco Tafani and Sergio Valente and Antonello Mai",

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Mellini, P, Marrocco, B, Borovika, D, Polletta, L, Carnevale, I, Saladini, S, Stazi, G, Zwergel, C, Trapencieris, P, Ferretti, E, Tafani, M, Valente, S & Mai, A 2018, 'Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells', Philosophical Transactions of the Royal Society B: Biological Sciences, vol. 373, no. 1748, 20170150. https://doi.org/10.1098/rstb.2017.0150

TY - JOUR

T1 - Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells

AU - Mellini, Paolo

AU - Marrocco, Biagina

AU - Borovika, Diana

AU - Polletta, Lucia

AU - Carnevale, Ilaria

AU - Saladini, Serena

AU - Stazi, Giulia

AU - Zwergel, Clemens

AU - Trapencieris, Peteris

AU - Ferretti, Elisabetta

AU - Tafani, Marco

AU - Valente, Sergio

AU - Mai, Antonello

PY - 2018/6/5

Y1 - 2018/6/5

N2 - Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4,6-dimethyl-2-oxo-1,2-dihy-dropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy.

AB - Novel pyrazole-based EZH2 inhibitors have been prepared through a molecular pruning approach from known inhibitors bearing a bicyclic moiety as a central scaffold. The hit compound 1o (N-((4,6-dimethyl-2-oxo-1,2-dihy-dropyridin-3-yl)methyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide) showed low micromolar EZH2/PRC2 inhibition and high selectivity towards a panel of other methyltransferases. Moreover, 1o displayed cell growth arrest in breast MDA-MB231, leukaemia K562, and neuroblastoma SK-N-BE cancer cells joined to reduction of H3K27me3 levels and induction of apoptosis and autophagy.

KW - Apoptosis

KW - Autophagy

KW - Enhancer of zeste homologue 2 inhibitors

KW - Epigenetics

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U2 - 10.1098/rstb.2017.0150

DO - 10.1098/rstb.2017.0150

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AN - SCOPUS:85045959069

SN - 0962-8436

VL - 373

JO - Philosophical Transactions of the Royal Society B: Biological Sciences

JF - Philosophical Transactions of the Royal Society B: Biological Sciences

IS - 1748

M1 - 20170150

ER -

Pyrazole-based inhibitors of enhancer of zeste homologue 2 induce apoptosis and autophagy in cancer cells

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